KR850001229B1 - Process for preparing 6- -aminoarylacetamido penicillanic acid - Google Patents

Abstract

6-Aminopenillanic acid (I) was converted to protected esters II [R = SiMe3, CHPh2, PhCH2, 4-O2NC6H4CH2, 4-MeOC6H4CH2, trichloroethyl, PhCOCH2, PhCOCH2, MeCOCH2, MeOCH2, 5-indanyl, 3-phthalidyl, CH(OCO2Et)Me, Me3CCO2CH2, AcOCH2 , which were used in the preparation of penicillins. I was treated with ClSiMe3 and Et3N, CO2 was introduced into the mixt., and the II (R = SiMe3) obtained was treated with D-(-)-4HOC6H4CH(NH2)COCl.HCl and PhNMe2 to give semi- synthetic penicillin derivatives, such as amoxicillin useful as a bactericide.

Description

Method for preparing 6-α-aminoarylacetamido phenylsilane acid

The present invention relates to a novel method for preparing phenylsilinides having so-called semisynthetic antimicrobial properties, such as ampicillin and amoxicillin, wherein the acyl side chain at the 6-position has an α-amino group.

The present invention relates to a compound of the formula (I) in the presence of an anhydrous inert organic solvent (preferably methylene chloride), preferably a weak base (preferably propylene oxide) at a temperature of -10 ° C or more (optimally about 20 ° C). It relates to a conventional process for producing penicillin, in which an equivalent molar amount of acid chloride or chloride hydrochloride (the latter is preferred) is added in portions and then B is converted to hydrogen.

Wherein B is an easily separated ester protecting group trimethylsilyl, benzhydryl, benzyl, p-nitrobenzyl, p-methoxybenzyl, trichloroethyl, phenacyl, acetonyl, methoxymethyl, 5-indanyl, 3 -Phthalidyl, 1-[(ethoxycarbonyl) oxy] ethyl, pivaloyloxymethyl or acetoxymethyl.

The conventional penicillin means those described above in the patent or scientific literature and excerpts.

The present invention also provides a compound solution of formula (II), wherein anhydrous carbon dioxide is used as a gas while maintaining the temperature range at room temperature or 0 ° -100 ° C. in the presence of an anhydrous inert organic solvent (preferably methylene chloride) until the reaction is completed. It relates to a process for the preparation of the compound of formula (I) consisting of addition to

Wherein B is as described above.

The present invention also provides a compound of formula (I ').

Wherein B is as defined in formula (I) above.

The present invention also provides a compound of formula (III) in the presence of an anhydrous inert organic solvent (preferably methylene chloride), preferably a weak base (preferably propylene oxide), at a temperature of -10 ° C. or higher (preferably about 20 ° C.). To an equimolar amount of D-(-)-α-aminoarylacetylchloride hydrochloride preferably D-(-)-2-phenylglycichloride hydrochloride or D-(-)-2-p-hydroxyphenylglycol A method for preparing 6-α-aminoarylacetamidophenylsilane acid, preferably ampicillin or amoxicillin, consisting of the addition of lysyl chloride hydrochloride (preferably the latter) and reaction.

An advantage of the present invention lies in the stability of the anhydrous acylation solution. Therefore, no detectable degradation of penicillin molecules occurred over long periods of storage at room temperature. This is in good contrast with the properties of the acylation solution in the conventionally described process. This stability makes it possible to carry out the acylation reaction at much higher temperatures (using room temperature) compared to the usual ampicillin production process which is typically performed at temperatures below 0 ° C., typically at about −10 ° C.

The present invention also adds anhydrous carbon dioxide gas while maintaining the trimethylsilyl 6-trimethylsilylaminophenicilanate solution in the presence of an inert organic solvent (preferably methylene chloride) while maintaining the temperature at 0 ° -100 ° C. until the reaction is complete. It relates to a process for preparing a compound of formula (III) consisting of

The compound of formula (III) is herein referred to as TMSO ₂ C. APA. TMS, 6-trimethylsilyloxycarbonylphenicylic acid TMS ester, bissilylated carbamate of SCA and 6-APA, and the like.

Reaction of carbon dioxide with 6-APA destroys 6-APA and produces, for example, 8-hydroxyphenicsilane acid, as described in US Pat. No. 3,225,033.

The key to obtaining quantitative yield of 6-trimethylsilyloxy carbonylaminophenicylanate trimethylsilyl ester (TMSO ₂ C. APA.TMS) is first to completely yield the 6-APA bis TMS precursor. This can be obtained by reacting 6-APA with hexamethyldisilazane (HMDS) as in the following reaction step.

Wherein HMDS is hexamethyldisilane, 6-APA is 6-aminophenicylic acid and TMCS is trimethylchlorosilane. Completion of the bistrimethylsilylation reaction can be tracked in advance using NMR. The 3-trimethylsilyloxycarbonyl group shows methylsilyl single peak at 0.31 ppm (TMS = 0) and the 6-trimethylsilylamine group shows methylsilyl single peak at 0.09 ppm.

The 6-APA trimethylsilylation reaction has only been carried out at present methylene chloride. However, other solvents may also be used, such as acetonitrile, dimethylformamide or HMDS.

The conversion of the trimethylsilylamino group to the trimethylsilyloxycarbonylamino group is carried out by foaming anhydrous CO ₂ into the reaction solution. This conversion can be easily deduced due to the fact that the trimethylsilylamino single peak at 0.09 ppm decreases as the new single peak of the trimethylsilyloxycarbonylamino group is shown at 0.27 ppm.

When the process of the present invention is used in the preparation of ampicillin, ampicillin anhydride, ampicillin trihydrate, amoxicillin, amoxicillin trihydrate, the final product is isolated, separated by known methods described in US Pat. Nos. 3,912,719, 3,980,637 and 4,128,547 and other patents and publications It can be purified.

The chloride used in the examples below can be replaced with other acid chlorides used to prepare conventional penicillins.

Acyl halides are therefore selected to introduce the desired acyl group at the 6-amino position, as described in US Pat. No. 3,741,959. That is, all of the special acyl radicals may be selected without being limited to the definition including the following general structural formula.

(1) R ^u C _n H _2n CO-: wherein R ^u is aryl (carboxy or heterocyclic), cycloalkyl, substituted aryl, substituted cycloalkyl, or a non-aromatic or mesoionic heterocyclic group , n is an integer of 1-4. Examples corresponding to the formula include phenylacetyl, substituted phenylacetyl (eg fluorophenylacetyl, nitrophenylacetyl, aminophenylacetyl, acetoxyphenylacetyl, methoxyphenylacetyl, methphenylacetyl, hydroxyphenylacetyl); N, N-bis (2-chloroethyl) aminophenyl propionyl; Diene-3- and 3-acetyl; 4-isooxazolyl and substituted 4-isooxazolylacetyl; Pyridylacetyl; Tetrazolylacetyl, a cydnonacetyl group, etc. are mentioned.

Substituted 4-isooxazolyl groups include 3-aryl-5-methylisoxazol-4-yl groups and the like, wherein the aryl group is phenyl or halophenyl (eg chloro- or bromophenyl). Acyl groups of this type are 3-0-chlorophenyl-5-methylisoxazol-4-yl-acetyl groups.

(2) C _n H _{2n + 1} CO-: wherein n is an integer of 1-7. The alkyl group may be straight or branched, and if desired, an oxygen or sulfur atom may be inserted and substituted with a cyano group or the like. Examples of such groups include cyano acetyl, hexanoyl, heptanoyl, octanoyl and butylthioacetyl.

(3) C _n H _2n-1 CO-: wherein n is an integer of 2-7. These groups are straight or branched and, if desired, oxygen or sulfur atoms can be inserted. Examples of such groups include allylthioacetyl and the like.

(4)

Wherein R ^u is the same as or benzyl as defined in (1), and R ^u and R ^w are the same or different and are hydrogen, phenyl, benzyl, phenethyl, or lower alkyl group.

Examples of such groups include phenoxyacetyl, 2-phenoxy-2-phenylacetyl, 2-phenoxypropionyl, 2-phenoxybutyryl, benzyloxycarbonyl, 2-methyl-2-phenoxypropionyl, p -Cresoxyacetyl and p-methylthiophenoxy acetyl and the like.

(5)

Where R ^u is the same as defined in (1) or benzyl, and R ^u and R ^w are the same as defined in (4). Examples of such groups include S-phenylthioacetyl, S-chlorophenylthioacetyl, S-fluorophenylthioacetyl, pyridylthioacetyl and S-benzylthioacetyl and the like.

(6) R ^u Z (CH ₂ ) _m CO-: where R ^u is as defined in (1) or may be benzyl, Z is oxygen or sulfur atom, m is an integer of 2-5 .

Examples of such groups include S-benzylthiopropionyl and the like.

(7) R ^u CO-: where R ^u is as defined in (1). Examples of such groups include benzoyl, substituted benzoyl (eg, aminobenzoyl), 4-isooxazolyl and substituted 4-isooxazolylcarbonyl, cyclopentanecarbonyl, sidoncarbonyl, naphthoyl and substituted naphthoyl ( Eg, 2-ethoxynaphthoyl) quinoxalinylcarbonyl and substituted quinoxalinylcarbonyl (eg 2-ethoxynaphthoyl) quinoxalinylcarbonyl and substituted quinoxalinylcarbonyl (eg 3- Carboxy-quinoxalinylcarbonyl), and the like. Other possible substituents of benzoyl and its derivatives include alkyl, alkoxy, phenyl or carboxy, alkylamido, cycloalkylamido, allylamido, phenyl (lower) -alkylamido, morpholinocarbonyl, pyrrolidinocar Phenyl substituted with carbonyl, piperidinocarbonyl, tetrahydropyridino, frpurylamido or N-alkyl-N-anilino, and the like. The positions of these substituents are 2- or 2- and 6-positions. Examples of such substituted benzoyl groups are 2, 6-dimethoxybenzoyl, 2-biphenylcarbonyl, 2-methylamidobenzoyl and 2-carboxybenzoyl. When R ^u is a substituted 4-isoxazolyl group, the substituents are as defined in (1). Examples of such 4-isoxazole groups include 3-phenyl-5-methylisoxazol-4-yl carbonyl, 3-0-chlorophenyl-5-methylisoxazol-4-yl carbonyl and 3- (2, 6 -Dichlorophenyl) -5-methylisoxazol-4-yl carbonyl and the like.

(8)

Wherein R ^u is as defined in (1) and X is obtained by reacting amino, substituted amino [eg, or 7-sided amino groups with aldehydes or ketones (eg, acetone, methylethylketone or ethylacetoacetate) Groups or acylamido], hydroxy, carboxy, esterified carboxy, triazolyl, tetrazolyl, cyano, halogeno, acyloxy (eg formyloxy or lower alkanoyloxy) or esterified hydroxy groups . Examples of such acyl groups include α-aminophenylacetyl, α-carboxyphenylacetyl and 2, 2-dimethyl-5-oxo-4-phenyl-1-amidazolidinyl.

(9)

Wherein R ^x , R ^y and R ^z are the same or different and can each be lower alkyl, phenyl or substituted phenyl. Examples of such acyl groups include triphenylcarbonyl groups and the like.

10

Wherein R ^u is as defined in (1) or is hydrogen, lower alkyl or halogen lower alkyl, and Y is oxygen or sulfur. Examples thereof include Cl (CH ₂ ) ₂ NHCO.

(11)

Where X is as defined in (3) and n is an integer from 1-4. Examples of such acyl groups include 1-amino-cyclohexanecarbonyl and the like.

(12) R ^w CH (NH ₂ ) · (CH ₂ ) _n CO

(n is an integer of 1-10), or NH ₂ · C _n H _2n Ar (CH ₂ ) _m CO

aminoacyl (m is 0 or an integer of 1-10, n is 0, 1, 2); R ^w is a hydrogen atom, an alkyl, aralkyl or carboxy group or a group as defined for R ^u , and Ar is an arylene group, ie p-phenylene or 1,4-naphthylene. Examples of such groups are described in British Patent Application No. 1,04,806. Groups of this type are δ-aminophenylacetyl groups. Still other acyl groups of this type include N-aminoadipoyl, which is a naturally occurring amino acid, and N-benzoyl-δ-aminoadifoyl, a derivative thereof.

(13) a substituted glycoxyyl group of R ^y CO · CO-; R ^y is an aliphatic, araliphatic, or aromatic group (e.g., thienyl group, phenyl group, mono-, di- or tri-substituted phenyl group; the substituent is one or more halogen atoms (F, Cl, Br, I ), A methoxy group, a methyl group, an amino group) or a bonded benzene ring.

If the acyl group contains an amino group, it is necessary to protect it during various reaction steps. The protecting group should be one that can be easily removed by hydrolysis without affecting the rest of the molecule, especially lactam and 7-amido bonds. The esterification group and amine protecting group at the 4-COOH position can be removed using the same reagent. Effective is to remove at the end of the process. Protected amine groups encompass urethane, arylmethyl (eg trityl) amino, arylmethyleneamino, sulfenylamino or enamine types. Enamine block groups are particularly useful in the case of 0-aminomethylphenylacetic acid. Such groups can generally be removed at low temperatures such as -80 ° C by one or more reagents selected from dilute inorganic acids (e.g. dilute hydrochloric acid), concentrated organic acids (e.g. concentrated acetic acid, trifluoroacetic acid) and liquid hydrogen bromide.

Preferred protecting groups are hydrolyzed with dilute inorganic acids (e.g. dilute hydrochloric acid) or strong organic acids (e.g. formic acid, trifluoroacetic acid) at 0-40 ° C, especially at room temperature (15-25 ° C), t-parts for easy removal It is a oxycarbonyl group.

Other preferred protecting groups can be separated by reagents such as zinc / acetic acid, zinc / formic acid, zinc / lower alcohol or zinc / pyridine. 2, 2, 2-trichloro ethoxycarbonyl groups and the like.

NH ₂ groups can be protected as NH ₃ ⁺ using amino acid halides as acid addition salts under conditions where the amino group is protonated.

The acid used to form the acid addition salt is preferred when pK _a (in water at 25 ° C.) is X + 1, where X is the pK _a value (in water at 25 ° C.) of the carboxyl group of the amino acid and monovalent acid is preferred as the acid. . In fact, HQ acids (see below) generally have pK _a of 3 or less (preferably 1 or less).

In particular, it has been found that acyl halides are salts of amino acid halides which result in more beneficial results for the process according to the invention.

The amino acid halide can be represented by the following formula,

H ₂ NR ₁ -COHal

Wherein R ₁ is a divalent organic group and Hal is chlorine or bromine. A salt of such an amino acid halide can be represented by the following formula

^{_{[H 3 NR 1 -COHal] +}} Q -

R ₁ and Hal are the same as defined above, Q ⁻ is the anion of the acid, and HQ has the pK _a value as described above.

The acid HQ is preferably a strong inorganic acid such as hydrochloric acid such as hydrochloric acid or bromic acid. Important amino acid halides due to penicillin antibiotics containing groups derived from them are DN- (α-chlorocarbonyl-α-phenyl) -methylammonium chloride, D- [PhCH (NH ₃ ) COCl] ⁺ Cl ⁻ (hereafter for convenience) D-α-phenylclichloride hydrochloride).

Prepared according to the invention and R ^u is the same as defined above

R ^u CH (NH ₂ ) CONH-

Penicillin containing an acylamido group reacts with a ketone in which R ² and R ³ are lower alkyl groups (C ₁ -C ₄ ) to yield compounds that are pushed to have the following groups.

Compounds of this type include hetacillin, sarpicillin, p-hydroxyhetacillin and sarmoxicillin.

Acyl groups described in US Pat. No. 4,014,648 column 7-20 are also included in this type.

When the acylation process of the present invention is used to produce penicillin, the final product is separated and purified according to conventional methods.

A is a compound of the formula wherein A is (CH ₃ ) ₃ Si- or an easily protected ester protecting group

Preferred acylchlorides of the invention used to acylate are as follows:

The definition of the group for the above formulas is as follows;

a) R is hydrogen, hydroxy, methoxy, R ¹ is hydrogen or methyl, and especially amino groups are blocked if they contain conventional block groups by quantization or the like.

b) R ¹ is hydrogen, hydroxy, acetoxy, R ¹ a is hydroxy and R ² is hydrogen, chloro or hydroxy, R ¹ a is hydrogen or acetoxy R ² is hydrogen.

e), f) R is phenyl, 4-hydroxyphenyl, 3, 4-dihydroxyphenyl or cyclohexa-1, 4-dien-1-yl.

h) R is phenyl, 4-hydroxyphenyl, 3, 4-dihydroxyphenyl or cyclohexadien-1-yl.

i) R ¹ is phenyl, 4-hydroxyphenyl, 3, 4-dihydroxyphenyl or cyclohexadien-1-yl and R ² is hydrogen or hydroxy.

r) R is as in h);

s) A is hydrogen or C _1-4 alkyl or CH ₃ SO ₂ −, X is oxygen or sulfur and R is as in e).

t) R is hydrogen or methyl.

v) R ¹ and R ² are each hydrogen, chloro or fluoro.

x) The definitions for R ₁ and R ₂ are as in b).

ee) The definitions for R ₁ and R ₂ are as in b), where R is hydrogen or cyanomethyl.

ii) The definitions for R ₁ and R ₂ are as in b).

jj) R is hydrogen or methyl.

ll) In particular, when a conventional block group is contained by quantization or the like, the amino group is blocked.

rr) The definitions for R ₁ and R ₂ are as in b).

ss) The definitions for R ₁ and R ₂ are as in b).

tt) The definitions for R ₁ and R ₂ are as in b).

The acid chloride is prepared under rapid conditions such as treatment by refluxing thionyl chloride and acid, but under mild conditions such as reacting a salt of acid with oxalyl chloride when sensitive groups (including sensitive block groups) are present. Are manufactured.

Example 1

1.23 mL triethylamine was added dropwise for 30 minutes to a mixture of 6-aminophenicsilane acid (6-APA), 10 mL CD ₂ Cl _2, and 1.13 mL trimethylchlorosilane at a temperature of 25-27 ° C.

Stirring was continued for 2 hours.

Anhydrous carbon dioxide gas was bubbled through the mixture for about 3 hours.

Finally, through NMR, it can be seen that 60% silylated carboxy of 6-APA (SCA) of the following formula exists.

This mixed liquid was placed in the refrigerator overnight. The next day 0.77 mL of N, N-dimethylaniline was added and cooled to -8 ° C.

1.2 g of D-(-)-p-hydroxy-2-phenylglycichloride hydrochloride (79% pure) was then added at the following ratio;

Time (min) Temperature (℃) Addition Amount (g)

0 -8 0.30

20 -4 0.30

40 -4 0.30

60 -4 0.30

120 +8

220 +15

310 +20

Going to the end of 310 minutes, thin layer chromatography was performed using 60% ethyl acetate, 20% acetic acid, and 20% solvent of water, indicating that amoxicillin is present.

1.0 mL D ₂ O was added to the cooled 2 mL final reaction mixture. After separation by centrifugation, the aqueous layer showed 78% of amoxicillin and about 20% 6-APA by NMR.

Example 2

A mixture of 5.4 g (0.025 moles) of 6-aminophenicylic acid, 6.2 ml of 93% hexamethyldisilazane (HMDS: 0.00275 moles) and 0.07 g (about 0.001 moles) imidazole in 40 ml of CH ₂ Cl ₂ It was refluxed through nitrogen for about 17.5 hours. Finally, 0.13 ml (about 0.001 mole) of trimethylchlorosilane (TMCS) is added and the solution becomes cloudy. After 7 hours reflux, NH ₄ Cl precipitates are found in the condenser. In this case, it can be seen that the amino and carboxyl groups were 100% silylated by NMR. Add 0.2 mL HMDS (0.00125 moles; about 5 mole%) about 0.06 mL TMCS (about 0.0005 moles), pass nitrogen and continue reflux for 17 h. The NMR spectrum at this time was the same as before the addition of a small amount of HMDS and TMCS. When anhydrous carbon dioxide was bubbled through the reaction mixture for 75 minutes at room temperature, and irradiated by NMR, it was found that there was no HMDS and more than 92% of silylated carboxy 6-APA (SCA) was present. At this time, 4.45 mL of N, N-dimethylaniline (DMA) (0.035 mol) was added and the mixture was cooled to -3 ° C. Then 5.65 g of D-(-)-2-phenylglycosyl chloride (95% purity, 0.026 mol) is added at the following ratio.

Time (min) Temperature (℃) Addition Amount (g)

0 -3 1.05

20 0 1.30

40 0 1.30

50 0 1.00

60 0 1.00

When the reaction was investigated by NMR, it was found that even after about 5 hours had elapsed since the reaction was started, the temperature was 3 ° C. The reaction mixture was kept on ice for 16 hours, then taken out of the freezer and stirred at room temperature (about 20-24 ° C.) for 3.5 hours. Large amounts of solids still exist. At the end, however, there was some turbidity. Extraction of D ₂ O from the sample followed by NMR showed ampicillin and 6-APA.

The reaction mixture was cooled to about 0 ° C., and 35 ml of ice water was added thereto, followed by stirring for 5 minutes. After impurity separation, the aqueous layer was washed with cold water and CH ₂ Cl ₂ . After separation, TLC shows that the aqueous layer is later than ampicillin and 6-APA and a new intermediate X appears in large areas.

The aqueous layer is adjusted to pH 3.0 with NH ₄ OH and ampicillin is added. Nautiloisobutyl ketone (35 ml) was added and the mixture was stirred, brought to pH 5.2 with NH ₄ OH, and stirred at 20 ° C. for one hour. It was stirred for another hour in an ice bath and frozen overnight. The precipitate of ampicillin was collected by filtration and washed sequentially with 25 ml cold water and 40 ml MIBK.

Lastly, 85 parts of isopropyl alcohol and 15 parts of water were washed with 40 ml, dried at 50 ° C., and examined by TLC, indicating that 4.5 g of ampicillin was produced.

Example 3

5.4 g 6-APA, 6.2 mL HMDS (93%) and 0.06 g imidazole mixture in 50 mL of CH ₂ Cl ₂ were refluxed under nitrogen for 18 hours. 0.1 ml TMCS was added.

Recirculation again for 2 hours yields a clear solution with NH ₄ Cl. Adding 0.1 ml TMCS showed only slight turbidity.

Reflow was continued while passing nitrogen for another 65 hours.

The temperature of this mixed solution was brought to about 22 ° C. and the addition of anhydrous carbon dioxide was started. NMR after 75 minutes showed 0% bissilylated carbamate formation. 4.45 mL DMA and 5.6 g D-(-)-2-phenylglycichloride hydrochloride (97% purity) were added at the following ratios;

Time (min) Temperature (℃) Addition Amount (g)

0 20 1.35

20 20 1.30

32 20 1.00

48 20 1.00

75 20 1.00

After further stirring the mixture for 17 hours, thin layer chromatography was performed on the reaction mixture and the diluted reaction mixture (1 ml reaction mixture diluted with ₂ ml CH ₂ Cl ₂ ). A small range of ampicillin and a wide range of new intermediates X appeared.

The reaction mixture was cooled to 0 ° C., 40 ml of ice water was added, stirred for 5 minutes, the impurities were filtered, and then washed with water and CH ₂ Cl ₂ . The aqueous layer was separated, 10% was left for the sample and the rest was brought to pH 3.0 with NH ₄ OH, and ampicillin was added and stirred. 40 ml MIBK was added and stirred, brought to pH 5.2 with ammonium hydroxide, stirred at room temperature for 1 hour and then stirred in an ice bath for 1 hour. Crystals are extracted. After freezing overnight, the crystals were collected by filtration, washed sequentially with MIBK, water, 40 ml isopropanol-water (85-15), and dried at 45 ° C. to yield 6.25 g of ampicillin (6.8 g, 68% yield).

Example 4

To a mixture of 1.0 g APA and 1.13 ml TMCS in 10 ml CD ₂ Cl ₂ was added dropwise 1.23 ml TEA for 30 minutes, followed by stirring for 2 hours. Anhydrous carbon dioxide was bubbled through for 4 hours. At this time, it can be seen that about 55-60% carboxylation was shown by NMR. This mixed solution was frozen overnight. The next day, 0.77 mL DNA is added, then stirred, cooled to -8 ° C and 1.2 g of D-(-)-p-hydroxy-2-phenylglycichloride hydrochloride is added as follows.

Time (min) Temperature (℃) Addition Amount (g)

0 -8 0.30

20 -4 0.30

40 -4 0.30

60 -4 0.30

120 8

220 15

310 20

NMR irradiation at the end of 310 minutes reveals about 78% amoxicillin and about 20% 6-APA.

Example 5

Suspension was suspended in anhydrous methylene chloride (175 ml) at 25 ° C. with stirring of anhydrous 6-aminophenicsilane acid (10.0 g, 46.24 mmol, 1.0 equiv). Triethylamine (10.76 g, 106.36 mmol, 2.30 equiv) was added at 25 ° C. followed by trimethylchlorosilane (11.70 g, 107.75 mmol, 2.33 equiv) maintaining the temperature below about 32 ° C. for 10-15 minutes. After stirring for 20-30 minutes, the mixed solution with precipitated triethylamine hydrochloride was stirred for 20-30 minutes and analyzed for complete silylation by 80 MHz NMR. The mixture was passed through anhydrous carbon dioxide at 20 ° C. for about 2 hours and then analyzed by 80 MHz NMR to determine whether complete carboxylation occurred. More gasification is sometimes needed. The volume of the carboxylation mixture was prepared at about 175 ml with anhydrous methylene chloride as needed. After carboxylation was completed, the slurry was treated with propylene oxide (2.95 g, 3.56 ml, 50.87 mmol, 1.1 equiv) and cooled to 0.5 ° C. D-(-)-2- (p-hydroxyphenyl) glycylchloride hydrochloride hemidoxane sorbate was added in 5 portions of 2.71 g at about 2 ° C (total 13.54 g (50.87 mmol, 1.1 equiv) Added). Acid chlorides in each part were dissolved before the next addition was made. It takes about 20 minutes for each part, and this ratio addition is very important. The final acylated mixture was tested for undissolved acid chloride hydrochloride. The mixture was kept at 0-5 ° C. for 30 minutes and then treated with cold non-ionized (DI) water (100 ml) at 0-5 ° C. for 10 minutes with high speed stirring. The mixture was separated and the methylene chloride was removed from the dense layer. The mixture was filtered through a thin coating of diatomaceous earth and the cake was washed with non-ionized chilled water (15 ml). The dense organic layer was completely removed prior to crystallization. The clear yellow solution (pH: 2-2.5) was brought to pH 3.5 at 0-5 ° C. The slurry was kept at 0-5 ° C. for 40 minutes and brought to pH 4.8-5.0 and crystallized for 2 hours. The slurry was filtered, the collected solid amoxicillin was washed with a 1: 1 isopropanol / water mixture and the cake washed with methylene chloride (30 ml) to yield about 13.5 g (70%) of dimoxicillin trihydrate.

Finish stirring and look for any solids in the bottom of the flask.

Make sure the slurry is no higher than 5 ° C to avoid mistakes in this experiment and the results.

Example 6

6-aminophenicylanic acid (108 g: 0.5 mole), 1.0 g imidazole (0.017 mole), 800 ml anhydrous methylene chloride and 120 ml (0.56 mole) HMDS (about 98% pure) were stirred and heated to reflux for 3.3 hours. . This reaction passes anhydrous nitrogen gas through reflux to exhaust the NH ₃ produced in the reaction. 2.0 ml (0.16 mole) trimethylchlorosilane (TMCS) was added. Again reflux was continued under nitrogen gas for 19 hours. Sublimed ammonium chloride in the condenser was removed and 2.6 ml trimethylchlorosilane (0.0206 mol) was added. The reflux was continued under nitrogen gas passage for 34 hours. The volume of the reaction mixture was brought to 1000 ml with anhydrous methylene chloride. NMR showed 100% silylation of amino and carboxyl groups in 6-aminophenicylanic acid. The solution was left for 9 days after being covered with nitrogen gas. NMR again demonstrated the 100% silylation and stability thereof.

After stirring, the carbon dioxide was bubbled through for about 90 minutes. NMR at 20-22 ° C. showed that bistrimethylsilyl 6-aminophenicylic acid was 100% converted to bistrimethylsilylcarboxy 6-aminophenicylanic acid (SCA).

This final mixture was used for the acylation experiment described below. In this solution, the compound shows the structure

NMR showed that even after 9 days, bistrimethylsilylcarboxy 6-aminophenic carboxylic acid was stable.

100 ml of the final mixture (SCA equivalent of 10.8 g of 6-aminophenicylanic acid; 0.05 mol) was stirred at 22 ° C. and 8.0 g of TEA.HCl (0.058 mol) and 4.2 ml of propylene oxide (0.06 mol) (US patent) No. 3,741,959).

Some TEA.HCl precipitated. This mixed solution was stirred and cooled to 3 ° C.

15.5 g of D-(-)-p-hydroxyphenylglycichloride hydrochloride hemidioxane sorbate (79% purity: 0.055 mol) was added at the following ratio;

Amount (g) Time (min) Temperature (℃)

3.0 0 +3

3.0 7 +2

3.0 20 +2

6.5 33 +2

15.5

After 70 minutes, the reaction mixture was added to about 50 ml ₂ ml 1.0 ml D ₂ O to reduce the viscosity. NMR analysis of the aqueous layer after centrifugation showed about 6% unacylated 6-aminophenicylanic acid.

After 10 minutes, the reaction mixture was transferred to a 600 ml beaker and washed with 50 ml methylene chloride. Adding 60 ml of non-ionized ice water while stirring in an ice bath yields a solution of pH 1.0 of two phases with no solids.

15.0 ml of liquid anion exchange resin ("LA-1") is added to the two phase system with stirring at pH 2.0. Then crystallization begins.

Additionally 10.0 ml LA-1 resin was added slowly for about 5 minutes. PH was 3.0 at this time. After adding 0.15 g of NaBH ₄ , a resin of 5.0 ml LA-1 was added (the pH at this time: 4.5).

After stirring was continued, 1.0 g NaHSO ₃ in 4.0 ml water was added dropwise. 10.0ml LA-1 resin was added to increase the pH. The total LA-1 resin was 40 ml and the peak pH was 5.6. Then add 5.0 ml acetone. At this time, 1.5 g NaHSO ₃ dissolved in 6.0 ml of water was added for 30 minutes. Stirring was continued in the bath and the precipitated product was filtered off and the cake was washed successively with 50 ml methylene chloride, 40 ml water, 100 ml isopropyl alcohol-mol (80:20) and 100 ml methylene chloride. Drying the cake at atmospheric pressure and 45 [deg.] C. yielded 18.2 g of ethoxycillin trihydrate, 87% yield for 6-aminophenicylanic acid, corrected for 1% sample yields approximately 88%. .

"LA-1" liquid anion exchange resin is a mixture of secondary amines having the following structure.

Wherein each of R ¹ , R ² and R ³ is an aliphatic hydrocarbon radical and the total [carbon atoms of 11 to 14 of R ¹ , R ² and R _3] . This unusual mixture of secondary amines classified as "Liquid Amine Mixture No. 1" is a clear amber liquid with the following physical properties.

The viscosity at 20 ° C. is 0.845 cps; Refractive index of 1.467 at 25 ° C; At 10 mmHg, up to 4% at 160 ° C, 5% at 160-210 ° C, 74% at 210-220 ° C and 17% above 210 ° C.

Example 7

Trimethylsilyl 6-trimethylsilyloxycarbonylaminophenicinate (0.54 g, 2.497 mmol) in methylene chloride solution (5.0 ml) was treated with triethylamine hydrochloride (0.20 g, 1.45 mmol) and propylene oxide (0.162 g) at 25 ° C. , 2.75 mmol) in turn. The mixture was stirred at 25 ° C. for 20 minutes to facilitate reaction of most triethylamine hydrochloride solutions. Phenoxyacetylchloride (0.43 g, 2.75 mmol) was added dropwise at 25 ° C. and the mixture was stirred at 25 ° C. for 30 minutes. Taking a sample and analyzing it with carbon -13 nuclear magnetic resonance at 20.0 MHz, it can be seen that the complete loss of phenoxyacetylchloride and APA carbamate and the production of penicillin V trimethylsilyl ester. The production of penicillin V trimethylsilylester was demonstrated by spectral comparison with similar samples prepared by silylating penicillin V free acid with triethylamine and trimethylchlorosilane. The output measured by CMR was 85 to 90%.

Similar preparations for equimolar reagents and suitable acid chlorides include clooxacillin, diclooxacillin, staphcillin and naphcillin. The CMR data of these acylation mixtures yielded extremely clear acylated mixtures calculated to be at least 85%.

Example 8

B is trimethylsilyl, benzhydryl, benzyl, p-nitrobenzyl, p-methoxybenzyl, trichloroethyl, phenacyl, acetonyl, methoxymethyl, 5-indanyl, 3-phthalidyl, 1- [ (Ethoxycarbonyl) oxy] The compound of formula (I ') which is an easily separable ester protecting group selected from the group consisting of entyl, pivaloyloxymethyl and acetoxymethyl may also contain a block group according to the present invention. After reacting with a reagent which is an acid chloride or an acid chloride hydrochloride, the block group is removed to prepare the next compound as required.

Almecillin; Armesyline; Azidocillin; Azocillin; Bacampacillin;

Carpecillin; Carindacillin; Cyclacillin; Clometocillin; Clooxacillin; Ticlooxacillin;

Epicylin; Fluorooxacillin (flucoloxacillin); Purbucillin; Hetacillin;

Isopropicillin; Methicillin; Mezlocillin; Naphcillin; Oxacillin; Penbenicillin;

Piperacillin; 3, 4-dihydroxy piperacillin; Perbenicillin; Pibampicillin;

Prazocillin; Sarmoxicillin; Sarpicillin; Ticarcillin; Sodium cresyl; Tacarcillin; Carbenicillin; Carpecillin; Fibracillin and

Example 9

Scheme

Wherein BSU is bis-trimethylsilylurea.

material

Based on 1.0 kg of crystallized 6-aminophenicylic acid.

It is assumed that the purity of 6-aminophenicylanic acid is 100%.

The amount of urea added should be measured to exactly react with the excess of tetraethylamine and the two materials react (first react with TMCS to yield HCl, yielding tetraethylamine, HCl (and BSU). It is important that urea be added to the silylated 6-APA.

stability

fair

Keep anhydrous.

1. Add 1.0 kg of 6-APA (4.63 mol) to 10.0 L of anhydrous methylene chloride (K.F. mol <0.02%) and stir gently. The sides of the vessel are washed with 1.0 L of anhydrous methylene chloride to wash off the attached 6-APA. 1.371 L (10.80 mole) of trimethylchlorosilane (TMCS) is added and then washed with 0.5 L of anhydrous methylene chloride for complete conversion of TMCS. Cover with anhydrous nitrogen. Maintain at 25 ° C.

2. Add 1.482 L of anhydrous triethylamine over 20-30 minutes, hold at 25-30 ° C., wash the measuring vessel and wash the funnel twice with anhydrous methylene chloride for complete conversion.

The total wash is 10 liters.

3. After complete addition of TEA, continue stirring for one hour to complete the silylation, then take the sample and leave. Precipitates if insoluble 6-APA is present TEA-HCl is present in the stomach.

4. After adding 38.9 g (0.65 mole) powdered urea, slowly stir the slurry and cover with nitrogen. It is to be noted that when the slurry is stirred for 1.5 hours and 1.5 hours have elapsed, urea is not present and the temperature is 25 ° C.

5. After stirring the slurry, add anhydrous CO ₂ gas, pass CO ₂ in the laboratory for 3 hours and use a condenser to prevent the loss of methylene chloride by evaporation.

NMR shows that 100% carboxylation was achieved.

In experiments this can be done under reduced pressure.

6. Add 0.389 L (5.56 mol) propylene oxide to the slurry, wash with 100 mL methylene chloride and cover with nitrogen. Cool to 0 ° C.

7. D-(-)-p-hydroxyphenylglycosyl chloride of 4.63 moles ^* divided in five. HCl hemidioxane sorbate is added every 25-30 minutes. The temperature at this time is maintained at 0 ° -3 ° C. The slurry is stirred at 0 ° -3 ° C. for 2 hours and samples are taken for thin layer chromatography. CO ₂ -gas is released during the reaction. Lighten the reaction.

* The weight of X-18-17 is based on purity: 4.63 mol of 79% pure city is 1306 grams.

8. Increase the mixing ratio and add 5.6 L of non-ionized-degassed to 5 ° C. Stir for 10 minutes. The mixing behavior should continue lightly after the initial addition of water and solution, which reduces emulsion formation. In the experiment, separation occurs into the two layers. If the quenching step is maintained at 0 ° -5 ° C. the hydrochloride of the product sometimes results in crystallization emulsion formation problems.

In this case, the process may be changed as necessary.

For example, the aqueous layer may be separated and processed into amoxicillin through filtration. However, in the present invention, no filtration or separation is necessary. Crystallization can be carried out directly through the addition of LA-1 resin as described below.

9. Add 1.0 L LA-1 (100%) for 5 minutes and stir to raise temperature to 12 ° C. After stirring, 0.5 L LA-1 resin was added over 5 minutes, at which time crystallization took place. Continue adding 1.0 L of LA-1 over about 10 minutes, raising the temperature to 18 ° C. At this time, the pH is 4.0. 0.092 liter of 50% ethylenediaminetetraacetic acid tetrasodium saline solution was added and stirred, followed by slow addition of LA-1 over 30 minutes, followed by 2700 ml LA-1 in 50 ml portions. The total LA-1 needed for this experiment is 3.0-3.05. pH is 5.4 and temperature is 18 ° C.

10. Add 11.5 g of NaHSO ₃ dissolved in about 200 mL of non-ionized-degassate to the slurry (this addition is not necessary if the product is of good color).

11. Stir the biphasic slurry and add 8.0 L of methylene chloride. Stir at 18-20 ° C. for 1 hour.

12. Cool the slurry to 0 ° -5 ° C. and hold for 2 hours in ionicity.

13. Collect the slurry by filtration. The cake is washed with 10.0 L of methylene chloride to remove LA-1 methylene chloride.

14. Wash the cake with 4.0 l of cooled (0 ° -5 ° C.) degassed-non-ionized product. Collect the wash in combination with the mother liquor. Do not mix the following washes.

15. Wash the cake with 6.5 L of 80% isopropanol-20% (DDI) water (5.32 L IPA-1.3 L DDI-H ₂ O).

16. Wash the cake with 4.0 L of isopropanol.

17. Wash the cake with 5.0 L of methylene chloride.

18. Dry the cake at 40-45 ° C.

19. Yield 85% of stoichiometric amount 1.65kg.

Using 1.05 moles of X-18-17 per 6-APA moles yields 86.5%. It has a Klett color of less than 50.

Thin layer chromatography of 10% solution shows a small amount of amoxicillin. The product itself may be suitably used in the formulation.

Claims (1)

6-α-aminoarylacetamidophenylsilane acid, characterized in that the compound of formula (III) Manufacturing method.